Wiring the brain: the possible key to effective obesity treatments

By
Jamie Pandey

For people struggling with weight loss, it can be frustrating when current treatments for obesity are neither helpful nor low-risk.

“A lot of pharmaceuticals aren’t very effective, and many have serious side effects,” says O’Connell, an assistant professor at The Jackson Laboratory (JAX). “Gastric bypass surgery can be really effective, but it’s highly invasive and can trigger complications.”

Obesity in the United States has been on the rise for many years, followed closely by its consequences — diabetes, stroke, heart disease and other health risks. Though exercise, diet and lifestyle all play key roles in obesity, it all starts with the brain.

“If we are successful we will find a way to cure obesity by making it easy for people to change their diet and change their lifestyle, because that’s the hard part,” O’Connell says.

She notes that currently available pharmaceuticals targeting obesity are limited in their effectiveness and often come with serious side effects, and so are primarily used only when their benefits outweigh their risks, Complicating the issue: Many health problems can frequently be the cause for obesity, making it even more difficult for those with chronic illnesses to maintain a healthy weight.

O’Connell recently received a $1.6 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases to allow her to continue to investigate the role of the brain — specifically the arcuate nucleus of the hypothalamus (ARH) — and how it regulates the appetite.

O’Connell has several peer-reviewed publications in prestigious journals such as Proceedings of the National Academy of Sciences (PNAS) and Nature Scientific Reports. Her most recent papers demonstrate that, in obese mice, the ARH is not as responsive to the appetite suppressant leptin compared to normal-weight mice. Put simply, O’Connell is searching for why the body does not listen when the brain is communicating that it should not be hungry.

While most scientists in the field are neuroendocrinologists (studying the nervous system and the hormones it produces), O’Connell is an electrophysiologist, who studies how electricity flows through neurons to communicate with the body, and how hormones interact with parts of the brain associated with the regulation of food intake.

One aspect of O’Connell’s research is investigating how certain obesity-targeting drugs work in mouse models. Obesity is sometimes caused by genetic defects, as seen in a range of conditions called ciliopathies, some of which, like Bardet-Biedl Syndrome, cause uncontrolled appetites. Researchers believe that these conditions involve defective neurons lacking normal signaling capabilities. O’Connell is testing several potential drug treatments to see if they can bypass the nonfunctioning neurons and enlist other, healthy neurons. One promising drug candidate is setmelanotide, which appears to work effectively to compensate for the defective neurons without causing hypertension or other adverse effects.

O’Connell also studies astrocytes, neurons that have numerous structural and functional roles in the brain, and their role in obesity. Many currently available obesity drugs are unable to pass through a filtering mechanism in the brain called the blood-brain barrier, which is formed by astrocytes and other cell types. She has found that setmelanotide is capable of passing through this barrier, pointing the way to a better approach to obesity drug development.

Highlighting the breadth of her work, O’Connell intends her research to provide new therapies not only for obesity but also “for all kinds of other diseases that affected by body weight, by diet, by lifestyle.”

Adult brains are not as “plastic” or capable of change as children’s brains, O’Connell notes. “Figuring out a way to rewire the adult brain could help adults change their lifestyles by helping their brains make the more difficult, but healthier, choices.”

With the worldwide increase in hypertension, diabetes, and other conditions associated with obesity, the results from O’Connell’s research at JAX may be just what the doctor will order.